Evidence of Epistatic Interactive Effects of HK1 and GCK Genes on Circulating Hemoglobin A1c Levels

BackgroundHemoglobin A1c (HbA1c), an important diagnostic biomarker for type 2 diabetes (T2D), is also associated with aging, cognitive performance, and mortality. To identify epistatic interactions, we assessed 133 known gene variants associated with HbA1c among 3,778 non-diabetic subjects of European ancestry in the Long Life Family Study (LLFS). MethodsWe applied Bayesian Imputation Based Association Mapping (BIMBAM) to identify significant pairwise epistatic interactions among genetic variants that were previously shown to be associated with levels of HbA1c. To take into account confounding effects, we adjusted age, sex, field centers, body mass index (BMI), and genetic principal components (PCs). ResultsThis analysis yielded seven pairs with log10(BF)>10; of those, six pairs were confirmed using a full-term mixed regression model. Specifically, these included significant interactions of HK1-rs17476364 with variants in GCK (rs2971670, rs4607517) or G6PC2 (rs560887), as well as between HK1-rs16926246 and the same variants (P values for each term [&le;] 7.14x10-3). All epistatic interactions between HK1 and GCK, and between HK1 and G6PC2 were replicated in two large independent studies (namely, Framingham Offspring Study, P < 0.05; Health and Retirement Study, P < 0.05). ConclusionThe present study revealed that HK1 and GCK interact to contribute to regulating levels of HbA1c and are likely to be involved in molecular mechanisms underlying healthy aging processes.